There is an urgent need for new antivirals for both treatment and control of dengue virus, given that over 50 million people are infected worldwide with dengue every year, including 500,000 cases of the more severe form of the disease, dengue hemorrhagic fever (DHF) and there are no approved vaccines or antiviral drugs available. Vaccine development is promising but faces several significant challenges including the need to balance protection against all four serotypes of the virus equally in order to avoid antibody-dependent enhancement of infection and risk of DHF. An antiviral drug that inhibits viral replication without increasing the risk for ADE would be extremely valuable for public health by providing a means to control outbreaks, as well as to government stockpiles for biodefense preparedness. The overall goal of the SIGA dengue program is to develop a small molecule therapeutic for the treatment and/or prevention of disease caused by dengue virus. A sensitive and specific high throughput screening (HTS) assay has been developed to evaluate compounds from the SIGA chemical compound library for inhibitory activity against dengue-2 (DEN-2) virus replication. Hits have been identified that are potent (EC50<5uM) and selective (CC50>25uM), with initial structure activity relationship in several series of related compounds. Quality hits were characterized for spectrum of activity, mechanism of action (MOA), preliminary absorption, distribution, metabolism and excretion (ADME) properties, preliminary biopharmaceutical properties, and tolerability. Based on this characterization two lead series were identified that have an optimal biological profile consistent with development of an anti-dengue drug. In this application chemical analogs of selected quality hits will be synthesized to improve the properties of the compounds leading to the nomination of a preclinical candidate which will enter into IND-enabling toxicology.